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Treatment of Psychiatric Symptoms Associated With Neurosyphilis
Treatment of Psychiatric Symptoms Associated With Neurosyphilis FRANCIS M. SANCHEZ, M.D. MARC H. ZISSELMAN, M.D.
There is currently no consensus on how to manage the psychiatric manifestations of neurosyphilis, despite the resurgence of this condition. The authors present five cases of neurosyphilis in inpatient psychiatric settings that manifested with predominantly psychiatric symptoms and were appropriately diagnosed and successfully treated with psychotropic medication concurrent with antibiotic therapy. A review of available data reveals that presently there are no specific guidelines to address psychiatric symptomatology in neurosyphilis. The authors see merit in the prudent use of psychotropic medication to achieve symptom stabilization. (Psychosomatics 2007; 48:440–445)
I
n 1999, the Center for Disease Control and Prevention published a national plan to eliminate syphilis from the United States.1 At that time, rates had declined to historic lows. However, the syphilis rate has climbed steadily since then, particularly among men, where there has been an 81% increase since 2000. In 2004, there were 7,980 reported cases of primary and secondary syphilis, with a rate of 4.7 cases per 100,000. Syphilis remains a significant health problem because of its facilitation of the transmission of HIV and the fact that it disproportionately affects African Americans living in poverty.2 Numerous studies have documented the approaches to the diagnosis and medical treatment of neurosyphilis. Definite neurosyphilis is diagnosed by positive cerebrospinalfluid (CSF) VDRL; probable neurosyphilis, by elevated
Received March 10, 2006; revised August 4, 2006; accepted August 9, 2006. From G. Werber Bryan Psychiatric Hospital, South Carolina Department of Mental Health, Columbia, SC; and Albert Einstein Medical Center, Philadelphia, PA. Send correspondence and reprint requests to Francis M. Sanchez, M.D., G. Werber Bryan Psychiatric Hospital, Staff Center C-D, 220 Faison Dr., Columbia, SC 29203. e-mail: francisgms@ yahoo.com 䉷 2007 The Academy of Psychosomatic Medicine
440
http://psy.psychiatryonline.org
CSF protein or leukocytosis, a history of exposure to syphilis, and no alternate explanation for the CSF findings. The classic presentations of neurosyphilis are memory loss, stroke, or spinal cord signs.3 Commonly, the condition begins with mild nonspecific personality changes and amnesia, which may evolve into dementia. It is recognized that the infection often manifests with psychiatric symptoms such as delusions, hallucinations, mood disorders, delirium, and aggression. Recent studies using single photon emission computed tomography (SPECT) and positron emission tomography (PET) have shown brain dysfunction, with significant decreases in cerebral blood flow throughout the cerebrum in patients who display psychiatric symptoms caused by the disorder.4 Despite our current knowledge of the condition, there is no literature assessing the treatment of the neuropsychiatric symptoms of the disease. Given the high morbidity associated with the symptoms, issues surrounding medication choice, dosing, duration of treatment, and approach to residual symptoms are significant. Our case series of five patients with psychiatric symptoms associated with neurosyphilis describes a treatment approach in the absence of rigorous published treatment protocols. Psychosomatics 48:5, September-October 2007
Sanchez and Zisselman Case Report 1 “Mr. B.,” a 49-year-old African American man with no past psychiatric history, was admitted to the inpatient psychiatric hospital after a 3-month progressive worsening of impulsive behavior, disorganized thinking, irritability, grandiosity, and insomnia. He was apprehended by police for trespassing and brought to a local emergency room, where he was threatening staff members and observed to be responding to internal stimuli. The South Carolina Department of Health and Environmental Control (DHEC) reported treatment for syphilis 14 years before this admission, but the patient had then been lost to follow-up. Collateral information revealed memory lapses, confusion, and behavioral changes in the preceding months. His physical and neurological examination and laboratory work-up were normal. Rapid plasma reagin (RPR) was positive, at 1:128, with reactive treponemal antibody testing. Brain CT revealed cerebral atrophy, with prominent sulci, and a lumbar tap confirmed neurosyphilis (Table 1). Mr. B had a 21-day course of daily IM procaine penicillin-G, because his behavior would preclude giving a course of IV treatment. Concurrently, his psychiatric symptoms were managed with haloperidol 10 mg twice daily and lorazepam 2 mg twice daily. He became significantly less agitated and was cooperative with his treatment, but he continued to show limited insight into his condition. Psychotropic medication was continued after completion of antibiotic therapy, and his Mini-Mental State Exam (MMSE) improved from 10 to 18 over a 12-week period. Residual deficits in attention and calculation, recall, three-stage command, sentencewriting, and figure-copying remained evident. He was discharged back to the care of his family on psychotropic medication and was subsequently lost to follow-up.
Case Report 2 “Mr. W” was a 37-year-old African American man committed to inpatient psychiatric hospital for fixed delusional thinking and aggressive behavior toward his family. He was convinced that he had a hole in his mouth and was afraid to eat because the food would fall to the ground. He had not slept or eaten for several days, would go into violent rages, and was threatening people around him. He had loose association and tangential thinking and was oriented only to person. He denied auditory or visual hallucinations. Mr. W walked with an unsteady gait and was incontinent of urine and feces. His MMSE score was 9, Psychosomatics 48:5, September-October 2007
with deficits in orientation, registration, calculation, recall, language repetition, three-stage command, writing, and copying. His neurologic exam revealed bradykinesia, stooped posture, and shuffling gait, but was otherwise nonfocal. His history reveals treatment for a positive RPR 10 years earlier, but he had been lost to follow-up. Current RPR was reactive, at 1:32, and neurosyphilis was confirmed by a lumbar puncture (Table 1). Brain computerized tomography (CT) showed dilated lateral ventricles, and brain magnetic resonance imaging (MRI) displayed prominent lateral ventricles bilaterally, normal third and fourth ventricles, gliosis of periventricular white matter, and no hydrocephalus. IV penicillin was administered for 14 days. Mr. W’s psychosis was managed with risperidone concentrate 3 mg daily, augmented after 2 weeks with divalproex sodium 500 mg BID (blood level: 71 lg/dL). With treatment, he showed improvement in his gait, incontinence problems, and psychiatric manifestations. Psychotropic regimen was continued throughout his 12-week hospitalization. His MMSE improved to 20. He displayed residual deficiencies in registration, calculation, recall, three-stage command, writing, and copying. Mr. W’s psychotropic medication regimen was still maintained at outpatient follow-up 10 months post-discharge. Case Report 3 “Mr. H” is a 41-year-old white man with no previous psychiatric history who presented selectively mute to the inpatient psychiatric hospital. He was often found wandering and was observed by peers to be talking to himself while at work. He had been described by his family as acting in a bizarre manner, not sleeping, eating, or talking for several weeks, and he was physically deconditioned. He would only nod occasionally to queries but was unwilling to take food or medication. Mr. H was uncooperative with hospital staff and only responded when a relative would visit and assist him with activities of daily living. RPR was positive, at 1:32. CSF analysis confirmed neurosyphilis (Table 1). Monotherapy for 2 weeks with risperidone 3 mg daily addressed the patient’s paranoia and guardedness; however, he required the addition of bupropion, extended release, 150 mg daily to address anhedonia and anergia, augmented with divalproex sodium 500 mg bid (blood level: 75 lg/ ml) for mood lability. He was given benzathine penicillin 2.4 million units IM weekly until confirmation of neurosyphilis with lumbar tap, after which he received procaine penicillin-G 2.4 million units IM daily with probenecid 500 mg po qid for 14 days. Psychotropic medication was conhttp://psy.psychiatryonline.org
441
442
wnl wnl wnl 3 4 5
RPR: rapid plasma reagin; wnl: we never looked; MMSE: Mini-Mental State Exam; VDRL: venereal disease research test; RBC: red blood cells; AFB: acid-fast bacilli; NG: no growth; MRI: magnetic resonance imaging; wnl: within normal limits. a Lab tests included complete blood count, comprehensive metabolic panel, HIV status, and urine drug screening.
7–25 18–30 20–21 NG NG NG 1:32 1:1,024 1:64 Ⳮ Ⳮ Ⳮ wnl wnl wnl
No bleeding or edema Atrophy, prominent sulci MRI: diffuse white-matter disease
? wnl ?
wnl wnl wnl
Neg. Neg. Neg.
? — ?
Neg. Neg. Neg.
— 1:32 1:64
10–18 9–20 NG NG 1:4 1:16 1:128 1:32 Ⳮ Ⳮ 1 2
Case
wnl wnl
wnl Bradykinesia; unsteady gait wnl wnl wnl
wnl wnl
Cerebral atrophy Dilated lateral ventricles
? ?
wnl wnl
Neg. Neg.
? ?
Neg. Neg.
CSF VDRL AFB Lymph RBC Titer RPR Lab Testsa Neurological Exam Physical Exam
TABLE 1.
Summary of Findings
Computed Tomography Finding
Cerebrospinal Fluid (CSF)
Protein
Glucose
MMSE Change
Culture
Case Reports
http://psy.psychiatryonline.org
tinued for 14 weeks as the patient showed improvement in his affect, energy, and insight. His MMSE score improved to 25/30 from a score of 7/30, with residual deficits in orientation, recall, and calculation. At 6-month follow-up, Mr. H was continued on the same psychotropic regimen by his primary-care provider. Case Report 4 “Mr. S,” a 33-year-old African American man with no previous psychiatric history, was committed to the inpatient psychiatric hospital after he displayed bizarre behavior, including bouts of impulsivity and aggression toward his family. He had a rapidly progressive deterioration in his illness, which began with wandering behavior and confusion coupled with insomnia and poor self-care. He appeared older than his stated age and was unkempt; he smelled of urine, he was tremulous and walked with an unsteady gait. Mr. S’s speech was mumbling, and he exhibited delusions of persecution, concrete thinking, illogical thought process, and perseveration He exhibited no insight into his condition; his MMSE score was 5/30. Physical and neurological examinations were nonfocal. Laboratories revealed reactive RPR, at 1:1,024 confirmed by reactive TPA. Brain CT revealed prominent sulci and atrophic changes for age. Records revealed partial treatment 15 years earlier for a positive RPR at South Carolina DHEC before he was lost to follow-up. Psychiatric treatment included quetiapine 600 mg qhs that addressed psychosis and insomnia and donepezil 10 mg daily for dementia, augmented after 4 weeks with divalproex sodium 500 mg bid (blood level: 70 lg/ml) for mood lability. Lorazepam 1 mg po was given for intermittent episodes of agitation and impulsivity. Mr. S received benzathine penicillin 2.4 million units IM weekly and, upon CSF confirmation of neurosyphilis, was then given penicillin IV for 2 weeks. He showed progressive improvement in MMSE score, to 18/30, and he was no longer exhibiting aggressive behavior, but still needed occasional verbal redirection from staff. The patient would decompensate when attempts were made to taper him off his psychotropic medications after 12 weeks of treatment, and he required placement in a long-term structured environment. Case Report 5 “Ms. A,” a 48-year-old African American woman with no previous history of psychiatric treatment, presented for evaluation of suicidality and memory problems at the Psychosomatics 48:5, September-October 2007
Sanchez and Zisselman Emergency Department. She elaborated ongoing symptoms of low mood, insomnia, anorexia, anhedonia, and anergia, and thoughts of “wishing the Lord would take me.” Two weeks before her presentation, she also had “visions of a white man” who would also tell her that God was coming to get her. Her MMSE score on admission was 20/30. She was not oriented to time or place and had poor registration and recall memory. Neurologic examination was nonfocal. Psychiatric management consisted of risperidone 3 mg qhs for her delusions and mirtazapine 30 mg qhs for her anhedonia, insomnia, and anergia. The patient was unable to complete psychological testing with a Bender-Binet test, but showed an IQ score of 50, which did not correlate with her educational background and previous functional status. RPR was positive, at 1:64, and neurosyphilis was confirmed by a lumbar puncture. MRI of the brain revealed minimal diffuse white-matter disease (Table 1). Treatment was initiated with IV penicillin-G for 21 days. The patient’s cognitive functioning remained unchanged throughout her 42-day hospitalization; however her psychiatric symptoms were remarkably improved at the time of transfer to a long-term facility for continuation of antibiotic treatment and psychotropic medications.
Discussion
This case series illustrates the need for prompt assessment when patients present with atypical psychiatric symptoms, particularly in the absence of past psychiatric history. The importance of a thorough history and mental-status examination, physical and neurological examination, and collateral information-gathering, as well as appropriate diagnostic testing, cannot be overemphasized when organic etiology is suspected. Although it may present as virtually any psychiatric disorder, a significant number of patients with neurosyphilis present with an insidious dementing process that leads to a progressive global deterioration in intellectual functioning.5 In their case series spanning 17 years, Danielsen et al.6 showed that median age at diagnosis was 47 years for men and 52 years for women, with the majority of patients (78%) being men. Although many of the patients presented in that series with neurological symptoms (36%), 17% initially presented with psychiatric symptoms or dementia. Our case series was predominantly men, with an average age of 41 years. Although protean, the CSF abnormalities that are most Psychosomatics 48:5, September-October 2007
characteristic of neurosyphilis include mononuclear pleocytosis and elevated protein. The diagnostic tests of choice in syphilis are serum and CSF nontreponemal and treponemal tests. Serum VDRL or RPR may be nonreactive in some cases of late neurosyphilis, whereas flourescent treponema antibody-absorbed (FTA-ABS) and microhemagglutination treponema pallidum (MHA-TP) are almost always reactive. Neurologic involvement occurs in up to 10% of patients with untreated syphilis.7 A diagnosis of neurosyphilis should be considered whenever an infected patient manifests any neurologic symptomatology. The notion of neurosyphilis being only a manifestation of tertiary syphilis is erroneous. Marra8 describes early and late stages of neurosyphilis, with the former affecting the meninges and the CSF and occurring in the first few months to years after infection. The treatment of choice for neurosyphilis is aqueous crystalline penicillin-G (3–4 million units IV every 4 hours) for 10–14 days, or procaine penicillin (2.4 million units IM once daily) plus probenecid (500 mg orally 4 times daily) for 10 to 14 days. Ceftriaxone is a suitable alternative (2 g IV once daily) for those with penicillin allergy.9 Our case series delineates the variability of presentations that neurosyphilis may manifest. Oftentimes, these patients are brought to the clinician’s attention in the psychiatric setting, be it an inpatient or community setting, or the emergency room. However, there are no definitive guidelines for proceeding with psychiatric treatment. The utilization of psychotropic medication in combination with appropriate antibiotic therapy appears to have been effective in reducing symptoms in the preceding cases. Haloperidol, as well as the atypical agents risperidone and quetiapine at or below recommended doses for schizophrenia appear to have clinical benefit for psychosis in this population. Furthermore, the addition of the antiepileptic and anti-manic agent divalproex sodium appeared to exert some benefit in mood stabilization and agitation. As in Alzheimer’s disease, no clear standard exists for the management of noncognitive neuropsychiatric symptoms of syphilis. Our case series represents clinical scenarios in which symptoms are of sufficient intensity to warrant pharmacologic intervention. In the absence of clinical trials, we believe an intuitive approach to treatment using Tariot’s psychobehavioral metaphor is warranted,10 identifying target symptoms and behavioral patterns that will point to the most appropriate classes of medications. Although often the pattern of behavioral signs and symptoms does not http://psy.psychiatryonline.org
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Case Reports meet syndromal criteria, it may be reminiscent of one with which we are familiar and know how to treat. This approach was recently endorsed by the American Association for Geriatric Psychiatry (AAGP).11 An expert consensus panel for using antipsychotic agents in older adults gave first-line recommendation for use of an antipsychotic alone with consideration for the addition of a mood-stabilizer for the treatment of agitated dementia with delusions.12 We also endorse their recommendation regarding the treatment of psychiatric symptoms associated with agitated dementia, where, if a patient has responded well to therapy, 3 to 6 months of treatment is advised before attempting to taper and discontinue the psychotropic medication.12 Risperidone is indicated in schizophrenia and acute manic or mixed episodes associated with bipolar disorder alone or in combination with lithium or valproate. In schizophrenia treatment, the original efficacy studies comparing different doses of risperidone indicated optimal effectiveness at doses of around 6 mg/day; however, clinical investigations and subsequent studies indicate that, for most adult patients, optimal doses are between 2 mg/day and 6 mg/day, with a minority of patients requiring higher doses.13 Recommendations using naturalistic studies, clinical audit, Phase 4 trials, and PET data suggest a target dose of 4 mg/day for most patients.14 Adjunctive agents such as combination mood-stabilizers or mood-stabilizers with antipsychotic agents are widely used in the treatment of manic symptoms.15 The use of risperidone in combination with a mood-stabilizer has been shown to be a safe therapy and more effective than a mood-stabilizer alone in the treatment of acute bipolar mania. Sachs et al.16 showed a greater reduction in the severity of mania on the Young Mania Rating Scale at endpoint in patients receiving risperidone and a moodstabilizer than in patients receiving a mood-stabilizer alone. The study also included patients receiving haloperidol plus a mood-stabilizer and also showed clinical improvement on most efficacy measures, but haloperidol was associated with substantially more extrapyramidal symptoms than risperidone.
Quetiapine is indicated for the treatment of acute manic episodes associated with bipolar I disorder as either monotherapy or adjunct therapy with lithium or divalproex, and in the treatment of schizophrenia. Quetiapine has been an effective antipsychotic when administered in doses of 300 mg–800 mg/day to address psychotic symptoms in the acute phase of schizophrenia.13 Divalproex sodium is indicated for the treatment of manic episodes associated with bipolar disorder. Initial studies have shown benefit in using divalproex sodium to treat agitation associated with dementia. Porsteinsson and Tariot17,18 have shown that the addition of divalproex sodium to the treatment regimen of patients diagnosed with dementia led to decreased scores on measures of agitation in comparison with placebo treatment. However, a more recent study did not show divalproex to benefit treatment of agitation in dementia.19
Conclusion
A literature search revealed a lack of evidence relating to the treatment of the psychiatric manifestations of neurosyphilis. In addressing specific symptoms in this population, there is apparent benefit in the judicious use of psychotropic medications. Given their side effects and potential toxicity, the risks and benefits of the administration of neuroleptic agents in patients with neurosyphilis must be reassessed on an ongoing basis. The lowest effective doses should be sought, and emergent side effects should first be treated by dose-reduction. Also, periodic attempts to reduce or withdraw these agents should be considered for all patients in the context of the probability of a relapse and the dangerousness of the target behaviors for which they were utilized. The authors would like to encourage other clinicians to report their experiences regarding the psychiatric care of patients with neurosyphilis. Increasing the knowledge-base is an essential step to developing pertinent guidelines for the treatment of this disease.
References
1. Division of STD Prevention, National Center for HIV, STD, and TB Prevention: National Plan to Eliminate Syphilis From the United States. Atlanta GA, Centers for Disease Control and Prevention, Oct 1999, accessed Dec 1, 2005. available at http:// www.cdc.gov/stopsyphilis/plan.htm 2. Division of STD Prevention, National Centers for HIV, STD, and
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TB Prevention: Report of the Syphilis Elimination Effort Consultation. Atlanta GA, Centers for Disease Control and Prevention, accessed Dec 12, 2005. available at http://www.cdc.gov/stopsyphilis/consultant-mtg-aug2005.htm 3. Timmermans M, Carr J: Neurosyphilis in the modern era. J Neurol Neurosurg Psychiatry 2004; 75:1727–1730
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Sanchez and Zisselman 4. Masayuki I, Mizukami K, Fujita T, et al: A case of neurosyphilis showing a marked improvement of clinical symptoms and cerebral blood flow on single photon emission computed tomography with quantitative penicillin treatment. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:417–420 5. Sobhan T, Rowe H, Ryan W, et al: Three cases of psychiatric manifestations of neurosyphilis. Psychiatr Serv 2004; 55:830–832 6. Danielsen AG, Weismann K, Jorgensen B, et al: Incidence, clinical presentation, and treatment of neurosyphilis in Denmark, 1980– 1997. Acta Derm Venereol 2004; 84:459–462 7. Brown DL, Frank JE: Diagnosis and management of syphilis. Am Fam Physician 2003; 68:283–290 8. Marra CM: Neurosyphilis. Curr Neurol Neurosci Rep 2004; 4:435–440 9. Jacobs RA: Infectious diseases: spirochetal, in Current Medical Diagnosis and Treatment, 44th Edition. Edited by Tierney LM, McPhee SJ, Papadakis MA. New York, Lange Medical Books, 2005 10. Tariot PN: Medical management of advanced dementia. J Am Geriatr Soc 2003; 51:5305–5313 11. Lyketsos CG, Colenda CC, Beck C, et al: Position Statement of the American Association for Geriatric Society Regarding Principles of Care for Patients With Dementia Resulting From Alzheimer’s Disease. Am J Geriatr Psychiatry 2006; 14:561–572
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12. Alexopoulos GS, Streim J, Carpenter D, et al: The Expert Consensus Panel for Using Antipsychotic Agents in Older Adults. J Clin Psychiatry 2004; 65(suppl2):1–105 13. Practice Guideline for the Treatment of Patients With Schizophrenia, 2nd Edition. American Psychiatric Association CME, released May, 2004; accessed Feb 2, 2006. available at http://psych.org/ cme/apacme/courses/index.cfm 14. Williams R: Optimal dosing with risperidone: updated recommendations. J Clin Psychiatry 2001; 62:282–289 15. Freeman MP, Stoll AL: Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry 1998; 155:12–21 16. Sachs GS, Grossman FS, Ghaemi N, et al: Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry 2002; 159:1146–1154 17. Porteinsson A, Tariot P, Jakimovich L, et al: Valproate therapy for agitation in dementia. Am J Geriatr Psychiatry 2003; 11:434–440 18. Porteinsson A, Tariot P, Erb R, et al: Placebo-controlled study of divalproex sodium for agitation in dementia. Am J Geriatr Psychiatry 2001; 9:58–66 19. Tariot PN, Raman R, Jakimovich L, et al: Divalproex sodium in nursing home residents with possible or probable Alzheimer’s disease complicated by agitation. Am J Geriatr Psychiatry 2005; 13:942–949
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There is currently no consensus on how to manage the psychiatric manifestations of neurosyphilis, despite the resurgence of this condition. The authors present five cases of neurosyphilis in inpatient psychiatric settings that manifested with predominantly psychiatric symptoms and were appropriately diagnosed and successfully treated with psychotropic medication concurrent with antibiotic therapy. A review of available data reveals that presently there are no specific guidelines to address psychiatric symptomatology in neurosyphilis. The authors see merit in the prudent use of psychotropic medication to achieve symptom stabilization. (Psychosomatics 2007; 48:440–445)
I
n 1999, the Center for Disease Control and Prevention published a national plan to eliminate syphilis from the United States.1 At that time, rates had declined to historic lows. However, the syphilis rate has climbed steadily since then, particularly among men, where there has been an 81% increase since 2000. In 2004, there were 7,980 reported cases of primary and secondary syphilis, with a rate of 4.7 cases per 100,000. Syphilis remains a significant health problem because of its facilitation of the transmission of HIV and the fact that it disproportionately affects African Americans living in poverty.2 Numerous studies have documented the approaches to the diagnosis and medical treatment of neurosyphilis. Definite neurosyphilis is diagnosed by positive cerebrospinalfluid (CSF) VDRL; probable neurosyphilis, by elevated
Received March 10, 2006; revised August 4, 2006; accepted August 9, 2006. From G. Werber Bryan Psychiatric Hospital, South Carolina Department of Mental Health, Columbia, SC; and Albert Einstein Medical Center, Philadelphia, PA. Send correspondence and reprint requests to Francis M. Sanchez, M.D., G. Werber Bryan Psychiatric Hospital, Staff Center C-D, 220 Faison Dr., Columbia, SC 29203. e-mail: francisgms@ yahoo.com 䉷 2007 The Academy of Psychosomatic Medicine
440
http://psy.psychiatryonline.org
CSF protein or leukocytosis, a history of exposure to syphilis, and no alternate explanation for the CSF findings. The classic presentations of neurosyphilis are memory loss, stroke, or spinal cord signs.3 Commonly, the condition begins with mild nonspecific personality changes and amnesia, which may evolve into dementia. It is recognized that the infection often manifests with psychiatric symptoms such as delusions, hallucinations, mood disorders, delirium, and aggression. Recent studies using single photon emission computed tomography (SPECT) and positron emission tomography (PET) have shown brain dysfunction, with significant decreases in cerebral blood flow throughout the cerebrum in patients who display psychiatric symptoms caused by the disorder.4 Despite our current knowledge of the condition, there is no literature assessing the treatment of the neuropsychiatric symptoms of the disease. Given the high morbidity associated with the symptoms, issues surrounding medication choice, dosing, duration of treatment, and approach to residual symptoms are significant. Our case series of five patients with psychiatric symptoms associated with neurosyphilis describes a treatment approach in the absence of rigorous published treatment protocols. Psychosomatics 48:5, September-October 2007
Sanchez and Zisselman Case Report 1 “Mr. B.,” a 49-year-old African American man with no past psychiatric history, was admitted to the inpatient psychiatric hospital after a 3-month progressive worsening of impulsive behavior, disorganized thinking, irritability, grandiosity, and insomnia. He was apprehended by police for trespassing and brought to a local emergency room, where he was threatening staff members and observed to be responding to internal stimuli. The South Carolina Department of Health and Environmental Control (DHEC) reported treatment for syphilis 14 years before this admission, but the patient had then been lost to follow-up. Collateral information revealed memory lapses, confusion, and behavioral changes in the preceding months. His physical and neurological examination and laboratory work-up were normal. Rapid plasma reagin (RPR) was positive, at 1:128, with reactive treponemal antibody testing. Brain CT revealed cerebral atrophy, with prominent sulci, and a lumbar tap confirmed neurosyphilis (Table 1). Mr. B had a 21-day course of daily IM procaine penicillin-G, because his behavior would preclude giving a course of IV treatment. Concurrently, his psychiatric symptoms were managed with haloperidol 10 mg twice daily and lorazepam 2 mg twice daily. He became significantly less agitated and was cooperative with his treatment, but he continued to show limited insight into his condition. Psychotropic medication was continued after completion of antibiotic therapy, and his Mini-Mental State Exam (MMSE) improved from 10 to 18 over a 12-week period. Residual deficits in attention and calculation, recall, three-stage command, sentencewriting, and figure-copying remained evident. He was discharged back to the care of his family on psychotropic medication and was subsequently lost to follow-up.
Case Report 2 “Mr. W” was a 37-year-old African American man committed to inpatient psychiatric hospital for fixed delusional thinking and aggressive behavior toward his family. He was convinced that he had a hole in his mouth and was afraid to eat because the food would fall to the ground. He had not slept or eaten for several days, would go into violent rages, and was threatening people around him. He had loose association and tangential thinking and was oriented only to person. He denied auditory or visual hallucinations. Mr. W walked with an unsteady gait and was incontinent of urine and feces. His MMSE score was 9, Psychosomatics 48:5, September-October 2007
with deficits in orientation, registration, calculation, recall, language repetition, three-stage command, writing, and copying. His neurologic exam revealed bradykinesia, stooped posture, and shuffling gait, but was otherwise nonfocal. His history reveals treatment for a positive RPR 10 years earlier, but he had been lost to follow-up. Current RPR was reactive, at 1:32, and neurosyphilis was confirmed by a lumbar puncture (Table 1). Brain computerized tomography (CT) showed dilated lateral ventricles, and brain magnetic resonance imaging (MRI) displayed prominent lateral ventricles bilaterally, normal third and fourth ventricles, gliosis of periventricular white matter, and no hydrocephalus. IV penicillin was administered for 14 days. Mr. W’s psychosis was managed with risperidone concentrate 3 mg daily, augmented after 2 weeks with divalproex sodium 500 mg BID (blood level: 71 lg/dL). With treatment, he showed improvement in his gait, incontinence problems, and psychiatric manifestations. Psychotropic regimen was continued throughout his 12-week hospitalization. His MMSE improved to 20. He displayed residual deficiencies in registration, calculation, recall, three-stage command, writing, and copying. Mr. W’s psychotropic medication regimen was still maintained at outpatient follow-up 10 months post-discharge. Case Report 3 “Mr. H” is a 41-year-old white man with no previous psychiatric history who presented selectively mute to the inpatient psychiatric hospital. He was often found wandering and was observed by peers to be talking to himself while at work. He had been described by his family as acting in a bizarre manner, not sleeping, eating, or talking for several weeks, and he was physically deconditioned. He would only nod occasionally to queries but was unwilling to take food or medication. Mr. H was uncooperative with hospital staff and only responded when a relative would visit and assist him with activities of daily living. RPR was positive, at 1:32. CSF analysis confirmed neurosyphilis (Table 1). Monotherapy for 2 weeks with risperidone 3 mg daily addressed the patient’s paranoia and guardedness; however, he required the addition of bupropion, extended release, 150 mg daily to address anhedonia and anergia, augmented with divalproex sodium 500 mg bid (blood level: 75 lg/ ml) for mood lability. He was given benzathine penicillin 2.4 million units IM weekly until confirmation of neurosyphilis with lumbar tap, after which he received procaine penicillin-G 2.4 million units IM daily with probenecid 500 mg po qid for 14 days. Psychotropic medication was conhttp://psy.psychiatryonline.org
441
442
wnl wnl wnl 3 4 5
RPR: rapid plasma reagin; wnl: we never looked; MMSE: Mini-Mental State Exam; VDRL: venereal disease research test; RBC: red blood cells; AFB: acid-fast bacilli; NG: no growth; MRI: magnetic resonance imaging; wnl: within normal limits. a Lab tests included complete blood count, comprehensive metabolic panel, HIV status, and urine drug screening.
7–25 18–30 20–21 NG NG NG 1:32 1:1,024 1:64 Ⳮ Ⳮ Ⳮ wnl wnl wnl
No bleeding or edema Atrophy, prominent sulci MRI: diffuse white-matter disease
? wnl ?
wnl wnl wnl
Neg. Neg. Neg.
? — ?
Neg. Neg. Neg.
— 1:32 1:64
10–18 9–20 NG NG 1:4 1:16 1:128 1:32 Ⳮ Ⳮ 1 2
Case
wnl wnl
wnl Bradykinesia; unsteady gait wnl wnl wnl
wnl wnl
Cerebral atrophy Dilated lateral ventricles
? ?
wnl wnl
Neg. Neg.
? ?
Neg. Neg.
CSF VDRL AFB Lymph RBC Titer RPR Lab Testsa Neurological Exam Physical Exam
TABLE 1.
Summary of Findings
Computed Tomography Finding
Cerebrospinal Fluid (CSF)
Protein
Glucose
MMSE Change
Culture
Case Reports
http://psy.psychiatryonline.org
tinued for 14 weeks as the patient showed improvement in his affect, energy, and insight. His MMSE score improved to 25/30 from a score of 7/30, with residual deficits in orientation, recall, and calculation. At 6-month follow-up, Mr. H was continued on the same psychotropic regimen by his primary-care provider. Case Report 4 “Mr. S,” a 33-year-old African American man with no previous psychiatric history, was committed to the inpatient psychiatric hospital after he displayed bizarre behavior, including bouts of impulsivity and aggression toward his family. He had a rapidly progressive deterioration in his illness, which began with wandering behavior and confusion coupled with insomnia and poor self-care. He appeared older than his stated age and was unkempt; he smelled of urine, he was tremulous and walked with an unsteady gait. Mr. S’s speech was mumbling, and he exhibited delusions of persecution, concrete thinking, illogical thought process, and perseveration He exhibited no insight into his condition; his MMSE score was 5/30. Physical and neurological examinations were nonfocal. Laboratories revealed reactive RPR, at 1:1,024 confirmed by reactive TPA. Brain CT revealed prominent sulci and atrophic changes for age. Records revealed partial treatment 15 years earlier for a positive RPR at South Carolina DHEC before he was lost to follow-up. Psychiatric treatment included quetiapine 600 mg qhs that addressed psychosis and insomnia and donepezil 10 mg daily for dementia, augmented after 4 weeks with divalproex sodium 500 mg bid (blood level: 70 lg/ml) for mood lability. Lorazepam 1 mg po was given for intermittent episodes of agitation and impulsivity. Mr. S received benzathine penicillin 2.4 million units IM weekly and, upon CSF confirmation of neurosyphilis, was then given penicillin IV for 2 weeks. He showed progressive improvement in MMSE score, to 18/30, and he was no longer exhibiting aggressive behavior, but still needed occasional verbal redirection from staff. The patient would decompensate when attempts were made to taper him off his psychotropic medications after 12 weeks of treatment, and he required placement in a long-term structured environment. Case Report 5 “Ms. A,” a 48-year-old African American woman with no previous history of psychiatric treatment, presented for evaluation of suicidality and memory problems at the Psychosomatics 48:5, September-October 2007
Sanchez and Zisselman Emergency Department. She elaborated ongoing symptoms of low mood, insomnia, anorexia, anhedonia, and anergia, and thoughts of “wishing the Lord would take me.” Two weeks before her presentation, she also had “visions of a white man” who would also tell her that God was coming to get her. Her MMSE score on admission was 20/30. She was not oriented to time or place and had poor registration and recall memory. Neurologic examination was nonfocal. Psychiatric management consisted of risperidone 3 mg qhs for her delusions and mirtazapine 30 mg qhs for her anhedonia, insomnia, and anergia. The patient was unable to complete psychological testing with a Bender-Binet test, but showed an IQ score of 50, which did not correlate with her educational background and previous functional status. RPR was positive, at 1:64, and neurosyphilis was confirmed by a lumbar puncture. MRI of the brain revealed minimal diffuse white-matter disease (Table 1). Treatment was initiated with IV penicillin-G for 21 days. The patient’s cognitive functioning remained unchanged throughout her 42-day hospitalization; however her psychiatric symptoms were remarkably improved at the time of transfer to a long-term facility for continuation of antibiotic treatment and psychotropic medications.
Discussion
This case series illustrates the need for prompt assessment when patients present with atypical psychiatric symptoms, particularly in the absence of past psychiatric history. The importance of a thorough history and mental-status examination, physical and neurological examination, and collateral information-gathering, as well as appropriate diagnostic testing, cannot be overemphasized when organic etiology is suspected. Although it may present as virtually any psychiatric disorder, a significant number of patients with neurosyphilis present with an insidious dementing process that leads to a progressive global deterioration in intellectual functioning.5 In their case series spanning 17 years, Danielsen et al.6 showed that median age at diagnosis was 47 years for men and 52 years for women, with the majority of patients (78%) being men. Although many of the patients presented in that series with neurological symptoms (36%), 17% initially presented with psychiatric symptoms or dementia. Our case series was predominantly men, with an average age of 41 years. Although protean, the CSF abnormalities that are most Psychosomatics 48:5, September-October 2007
characteristic of neurosyphilis include mononuclear pleocytosis and elevated protein. The diagnostic tests of choice in syphilis are serum and CSF nontreponemal and treponemal tests. Serum VDRL or RPR may be nonreactive in some cases of late neurosyphilis, whereas flourescent treponema antibody-absorbed (FTA-ABS) and microhemagglutination treponema pallidum (MHA-TP) are almost always reactive. Neurologic involvement occurs in up to 10% of patients with untreated syphilis.7 A diagnosis of neurosyphilis should be considered whenever an infected patient manifests any neurologic symptomatology. The notion of neurosyphilis being only a manifestation of tertiary syphilis is erroneous. Marra8 describes early and late stages of neurosyphilis, with the former affecting the meninges and the CSF and occurring in the first few months to years after infection. The treatment of choice for neurosyphilis is aqueous crystalline penicillin-G (3–4 million units IV every 4 hours) for 10–14 days, or procaine penicillin (2.4 million units IM once daily) plus probenecid (500 mg orally 4 times daily) for 10 to 14 days. Ceftriaxone is a suitable alternative (2 g IV once daily) for those with penicillin allergy.9 Our case series delineates the variability of presentations that neurosyphilis may manifest. Oftentimes, these patients are brought to the clinician’s attention in the psychiatric setting, be it an inpatient or community setting, or the emergency room. However, there are no definitive guidelines for proceeding with psychiatric treatment. The utilization of psychotropic medication in combination with appropriate antibiotic therapy appears to have been effective in reducing symptoms in the preceding cases. Haloperidol, as well as the atypical agents risperidone and quetiapine at or below recommended doses for schizophrenia appear to have clinical benefit for psychosis in this population. Furthermore, the addition of the antiepileptic and anti-manic agent divalproex sodium appeared to exert some benefit in mood stabilization and agitation. As in Alzheimer’s disease, no clear standard exists for the management of noncognitive neuropsychiatric symptoms of syphilis. Our case series represents clinical scenarios in which symptoms are of sufficient intensity to warrant pharmacologic intervention. In the absence of clinical trials, we believe an intuitive approach to treatment using Tariot’s psychobehavioral metaphor is warranted,10 identifying target symptoms and behavioral patterns that will point to the most appropriate classes of medications. Although often the pattern of behavioral signs and symptoms does not http://psy.psychiatryonline.org
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Case Reports meet syndromal criteria, it may be reminiscent of one with which we are familiar and know how to treat. This approach was recently endorsed by the American Association for Geriatric Psychiatry (AAGP).11 An expert consensus panel for using antipsychotic agents in older adults gave first-line recommendation for use of an antipsychotic alone with consideration for the addition of a mood-stabilizer for the treatment of agitated dementia with delusions.12 We also endorse their recommendation regarding the treatment of psychiatric symptoms associated with agitated dementia, where, if a patient has responded well to therapy, 3 to 6 months of treatment is advised before attempting to taper and discontinue the psychotropic medication.12 Risperidone is indicated in schizophrenia and acute manic or mixed episodes associated with bipolar disorder alone or in combination with lithium or valproate. In schizophrenia treatment, the original efficacy studies comparing different doses of risperidone indicated optimal effectiveness at doses of around 6 mg/day; however, clinical investigations and subsequent studies indicate that, for most adult patients, optimal doses are between 2 mg/day and 6 mg/day, with a minority of patients requiring higher doses.13 Recommendations using naturalistic studies, clinical audit, Phase 4 trials, and PET data suggest a target dose of 4 mg/day for most patients.14 Adjunctive agents such as combination mood-stabilizers or mood-stabilizers with antipsychotic agents are widely used in the treatment of manic symptoms.15 The use of risperidone in combination with a mood-stabilizer has been shown to be a safe therapy and more effective than a mood-stabilizer alone in the treatment of acute bipolar mania. Sachs et al.16 showed a greater reduction in the severity of mania on the Young Mania Rating Scale at endpoint in patients receiving risperidone and a moodstabilizer than in patients receiving a mood-stabilizer alone. The study also included patients receiving haloperidol plus a mood-stabilizer and also showed clinical improvement on most efficacy measures, but haloperidol was associated with substantially more extrapyramidal symptoms than risperidone.
Quetiapine is indicated for the treatment of acute manic episodes associated with bipolar I disorder as either monotherapy or adjunct therapy with lithium or divalproex, and in the treatment of schizophrenia. Quetiapine has been an effective antipsychotic when administered in doses of 300 mg–800 mg/day to address psychotic symptoms in the acute phase of schizophrenia.13 Divalproex sodium is indicated for the treatment of manic episodes associated with bipolar disorder. Initial studies have shown benefit in using divalproex sodium to treat agitation associated with dementia. Porsteinsson and Tariot17,18 have shown that the addition of divalproex sodium to the treatment regimen of patients diagnosed with dementia led to decreased scores on measures of agitation in comparison with placebo treatment. However, a more recent study did not show divalproex to benefit treatment of agitation in dementia.19
Conclusion
A literature search revealed a lack of evidence relating to the treatment of the psychiatric manifestations of neurosyphilis. In addressing specific symptoms in this population, there is apparent benefit in the judicious use of psychotropic medications. Given their side effects and potential toxicity, the risks and benefits of the administration of neuroleptic agents in patients with neurosyphilis must be reassessed on an ongoing basis. The lowest effective doses should be sought, and emergent side effects should first be treated by dose-reduction. Also, periodic attempts to reduce or withdraw these agents should be considered for all patients in the context of the probability of a relapse and the dangerousness of the target behaviors for which they were utilized. The authors would like to encourage other clinicians to report their experiences regarding the psychiatric care of patients with neurosyphilis. Increasing the knowledge-base is an essential step to developing pertinent guidelines for the treatment of this disease.
References
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Sanchez and Zisselman 4. Masayuki I, Mizukami K, Fujita T, et al: A case of neurosyphilis showing a marked improvement of clinical symptoms and cerebral blood flow on single photon emission computed tomography with quantitative penicillin treatment. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:417–420 5. Sobhan T, Rowe H, Ryan W, et al: Three cases of psychiatric manifestations of neurosyphilis. Psychiatr Serv 2004; 55:830–832 6. Danielsen AG, Weismann K, Jorgensen B, et al: Incidence, clinical presentation, and treatment of neurosyphilis in Denmark, 1980– 1997. Acta Derm Venereol 2004; 84:459–462 7. Brown DL, Frank JE: Diagnosis and management of syphilis. Am Fam Physician 2003; 68:283–290 8. Marra CM: Neurosyphilis. Curr Neurol Neurosci Rep 2004; 4:435–440 9. Jacobs RA: Infectious diseases: spirochetal, in Current Medical Diagnosis and Treatment, 44th Edition. Edited by Tierney LM, McPhee SJ, Papadakis MA. New York, Lange Medical Books, 2005 10. Tariot PN: Medical management of advanced dementia. J Am Geriatr Soc 2003; 51:5305–5313 11. Lyketsos CG, Colenda CC, Beck C, et al: Position Statement of the American Association for Geriatric Society Regarding Principles of Care for Patients With Dementia Resulting From Alzheimer’s Disease. Am J Geriatr Psychiatry 2006; 14:561–572
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12. Alexopoulos GS, Streim J, Carpenter D, et al: The Expert Consensus Panel for Using Antipsychotic Agents in Older Adults. J Clin Psychiatry 2004; 65(suppl2):1–105 13. Practice Guideline for the Treatment of Patients With Schizophrenia, 2nd Edition. American Psychiatric Association CME, released May, 2004; accessed Feb 2, 2006. available at http://psych.org/ cme/apacme/courses/index.cfm 14. Williams R: Optimal dosing with risperidone: updated recommendations. J Clin Psychiatry 2001; 62:282–289 15. Freeman MP, Stoll AL: Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry 1998; 155:12–21 16. Sachs GS, Grossman FS, Ghaemi N, et al: Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry 2002; 159:1146–1154 17. Porteinsson A, Tariot P, Jakimovich L, et al: Valproate therapy for agitation in dementia. Am J Geriatr Psychiatry 2003; 11:434–440 18. Porteinsson A, Tariot P, Erb R, et al: Placebo-controlled study of divalproex sodium for agitation in dementia. Am J Geriatr Psychiatry 2001; 9:58–66 19. Tariot PN, Raman R, Jakimovich L, et al: Divalproex sodium in nursing home residents with possible or probable Alzheimer’s disease complicated by agitation. Am J Geriatr Psychiatry 2005; 13:942–949
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